ABSTRACT/SUMMARY Individuals with cocaine dependence (CD) are characterized by motivation deficits and under-responsiveness to natural reinforcers. Enhancement of intrinsic motivation is a critical component in cognitive behavioral treatment of drug addiction. As part of the core limbic circuit, the hypothalamus is implicated in a wide range of motivated behaviors. On the other hand, the neural bases of intrinsic motivation and how hypothalamic circuit dysfunction contributes to motivation deficits in addiction remain largely unknown. Motivation hinges on an internal drive to engage in actions that do not dictate explicit or immediate reward. Extant studies in addiction neuroscience have focused on cerebral responses to drug cues and explicit reward, but there is a dearth of information regarding the neural bases of intrinsic motivation ? cerebral responses to motivated behavior independent of performance outcomes and reward. To address this gap of research, we will study CD and non-drug using controls (HC) in a behavioral paradigm that engages self choice and controls for performance outcomes and external reward. Self versus forced choice involves activation of the hypothalamus and ventromedial prefrontal cortex (vmPFC), suggesting the role of hypothalamus-vmPFC circuit in intrinsic motivation. Further, preclinical work showed distinct and interacting functions of the lateral hypothalamus (LH) and medial hypothalamus (MH). In human imaging, the LH and MH each responds to negative and positive emotions. Following an atlas of the human hypothalamus we distinguished resting state functional connectivity of the LH and MH, with LH and MH each connected to the dorsal anterior cingulate cortex and vmPFC. Importantly, compared to HC, CD showed altered LH and MH connectivity in association with the severity of cocaine use. Building on these findings, we will investigate how the hypothalamus responds to external emotional and intrinsic motivation challenges, with concurrent recording of physiological arousal. Specifically, in conjunction with an ongoing K25 study, we will examine a) how CD and HC differ in LH and MH responses each to negative and positive emotions and in MH/vmPFC responses to intrinsic motivation challenges; b) how CD and HC differ in task-modulated LH and MH functional connectivity in association with changes in physiological arousal; c) how hypothalamic dysfunction predicts relapse in cocaine addiction. By combining MR imaging and multiple behavioral paradigms to examine hypothalamus function, the study will provide critical information on motivation deficits in cocaine addiction.